Efficacy of Tibial Nerve Stimulation in Neurogenic Lower Urinary Tract Dysfunction Among Patients with Multiple Sclerosis: A Systematic Review and Meta-analysis

Objective: This study was performed to systematically review the current literature on the effects of transcutaneous tibial nerve stimulation and percutaneous tibial nerve stimulation on multiple sclerosis-induced neurogenic lower urinary tract dysfunction. Materials and methods: Medical databases including PubMed, Scopus, Embase, and Web of Science were systematically searched from inception to September 2022. Meta-analysis was carried out using the comprehensive meta-analysis tool. Results: Our inclusion criteria were met by 12 studies evaluating the effects of percutaneous tibial nerve stimulation/transcutaneous tibial nerve stimulation on multiple sclerosis-induced neurogenic lower urinary tract dysfunction. Comparing the post-intervention results to the baseline showed that the rate of frequency was decreased in both percutaneous tibial nerve stimulation and transcutaneous tibial nerve stimulation groups after intervention. The overall mean change of tibial nerve stimulation on frequency was –2.623 (95% CI: –3.58, –1.66; P < .001, I 2: 87.04) among 6 eligible studies. The post-void residual was decreased after treatment in both methods of tibial nerve stimulation, with an overall mean difference of –31.13 mL (95% CI: –50.62, –11.63; P = .002, I 2: 71.81). The other urinary parameters, including urgency (mean difference: –4.69; 95% CI: –7.64, –1.74; P < .001, I 2: 92.16), maximum cystometric capacity (mean difference: 70.95; 95% CI: 44.69, 97.21; P < .001, I 2: 89.04), and nocturia (mean difference: –1.41; 95% CI: –2.22, 0.60; P < .001, I 2: 95.15), were improved after intervention, too. However, the results of subgroup analysis showed no effect of transcutaneous tibial nerve stimulation on urinary incontinence (mean difference: –2.00; 95% CI: –4.06, 0.06; P = .057, I 2: 95.22) and nocturia (mean difference: –0.39; 95% CI: –1.15, 0.37; P = .315, I 2: 84.01). In terms of mean voided volume, the evidence was related to only percutaneous tibial nerve stimulation with a mean change of 75.01 mL (95% CI: –39.40, 110.61; P < .001, I 2: 85.04). Conclusion: Although the current literature suggests that tibial nerve electrostimulation might be an effective method for treating neurogenic lower urinary tract dysfunction, the evidence base is poor and derived from small, mostly nonrandomized trials with a high risk of bias and confounding.


Introduction
Neurogenic lower urinary tract dysfunction (NLUTD) is one of the most frequent complaints in multiple sclerosis (MS) patients. Approximately 90% of MS patients experience urologic symptoms 10 years after the outbreak of the disease, while 5%-10% of patients have bladder disturbances at the beginning of the disease. 1,2 Considering their troublesome nature, these symptoms can severely affect patients' quality of life (QoL). 3 The bladder dysfunction can be attributed to several pathophysiological pathways, including impulse blockage in demyelinated axons, conduction failure due to neuronal degeneration, and possible functional impairment of cytokines. 4 The first and the second pathology are related to damage in bladder control and the third pathology links the bladder disturbances to the dysfunction of receptors and neurotransmitters which are responsible for bladder control. In MS, NLUTD occurs as a consequence of spinal cord involvement above the sacral segment, leading to urinary symptoms including increased frequency and urgency of micturition, nocturia, incontinence, and inability to empty the bladder completely. The first 2 are suggested to be the most frequent ones. 5,6 Approaching the MS-induced NLUTD consists of a multidisciplinary method. For instance, intermittent self-catheterization offers one of the best methods of coping with incomplete bladder emptying and urinary retention. Medications including antimuscarinics benefit patients with frequency, nocturia, urgency, or urge incontinence. 7 Other approaches are available in cases where antimuscarinics are ineffective or poorly tolerated, including intradetrusor botulinum toxin, or nerve stimulation methods including tibial nerve stimulation (TNS) and sacral neuromodulation. [8][9][10] Neuromodulation is, as defined by the International Neuromodulation Society, the use of implantable and non-implantable electrical or chemical technologies to enhance the quality of human life and functioning. The use of neuromodulation has been increased recently, especially for managing chronic pain, musculoskeletal disorders, psychiatric disorders, and epilepsy. 10 Transcutaneous tibial nerve stimulation (TTNS) and percutaneous tibial nerve stimulation (PTNS) are 2 types of neuromodulation that have been proposed for the treatment of MS-related urinary disturbances. [11][12][13] These techniques rely on electrical stimulation of the tibial nerve to constrain the detrusor muscle. The most frequently reported intervention in the greater part of academic studies consists of 30-minute stimulation sessions performed every week for 10-12 weeks. 14 Having the importance of managing NLUTD and its high prevalence among MS patients in mind, this study aims to systematically review the current literature on the effects of TNS (PTNS/TTNS) on the MS-induced NLUTD.

Materials and Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement was followed when conducting this study to ensure accurate data reporting. 15 The protocol was registered in the International Prospective Register of Systematic Reviews under the code CRD42022360571.

Information Sources and Search Strategy
From their creation to September 2022, a number of medical databases, including PubMed, Scopus, Embase, and Web of Science, were thoroughly searched. They were then updated in October 2021. Google Scholar and all the references of the included studies were also checked for items that met the inclusion criteria, and those were imported to make sure there was complete saturation. The main search terms were as follows: "multiple sclerosis," "MS," "tibial nerve stimulation," "percutaneous electric nerve stimulation,", "PTNS," "transcutaneous electrical nerve stimulation," "TTNS," "neuromodulation," "neurogenic bladder," "urinary bladder," "overactive bladder," "urinary incontinence," and "neurogenic lower urinary tract dysfunction." The Endnote X20 citation manager software was used to import the search results for further exploration.

Eligibility Requirements
Two impartial reviewers conducted the eligibility evaluation (F.T. and S.H.). A third reviewer was consulted to settle any disagreements (H.S.). Studies were selected for further survey if they met all of the following criteria: (1) studies aiming to determine the effects of PTNS and/or TTNS on NLUTD in MS patients; (2) a population consisting of humans; and (3) available English full text.
Unoriginal articles including any type of reviews, conference proceedings, letters, and commentaries were excluded.

Quality Assessment
The quality of included studies was assessed through the Joanna Briggs Institute tools of critical appraisal, each individualized based on the methodology of the study. 16 In cases of disagreement, a third reviewer evaluated the study for confirmation after 2 authors independently evaluated the quality of the studies.

Data Collection Process and Data Items
In a predetermined Excel sheet, 2 authors (F.T. and H.S.) extracted the data from the included studies. From each of the included studies, the following information was taken: data on citations including the first author's name; the publication's year and place of publication; the number, condition, and age of patients; the condition of the control group; the type of intervention used; the number, length, and frequency of therapy sessions; the length of the follow-up period; and the main outcomes of measure.

Synthesis of Results
The comprehensive meta-analysis tool v3.7z was used to conduct the meta-analysis. For identifying heterogeneity within the studies, the Q statistic was used. Additionally, the I 2 statistic was used to calculate the effect of study heterogeneity. Low I 2 was defined as 25%, moderate as 25%-75%, and high as >75%. A fixed-effect model was used when there was no statistically significant difference in the heterogeneity (P < .05); otherwise a random effect model was applied.

Literature Search and Description of Studies
Up until September 2022, we discovered 3855 publications through the use of electronic databases, manual searches, and reference checking. After the duplicate studies were eliminated, 2194 studies underwent title/abstract screening. After reviewing the full texts of 41 articles, we determined that 12 studies satisfied our inclusion criteria and were included in this systematic review. A total of 8 studies were eligible for meta-analysis. In addition, 10 studies were found with mixed population; however, they did not separate data for the MS patients; therefore, we were unable to analyze their findings (Supplementary Table 1). The PRISMA flow diagram displays more details about the selection procedure ( Figure 1). Tables 1 and 2 show the characteristics and the quality of the included studies, respectively. Twelve clinical studies were included, which assessed the outcomes of TNS among MS population.

Summary of the Evidence
Seven studies used PTNS [17][18][19][20][21][22][23] and the other 5 used TTNS as the neuromodulation technique. [24][25][26][27][28] Five studies took place in Turkey, [18][19][20]26,25 2 studies in the United Kingdom, 22,23 and 1 in each of the following countries: Denmark, 17 Switzerland, 21 France, 24 and Bosnia and Herzegovina. 28 Three studies had a parallel control group-2 was a nonrandomized clinical trial with a control group consisting of pelvic floor muscle training 25,26 and the other 1 was a randomized clinical trial with a control group receiving 5 mg oxybutynin tablet twice a day for 3 months. 28 The Expanded Disability Status Scale score was reported in 9 studies and varied from the minimum of 3.40 to 4.8.
Furthermore, publications with mixed populations were reviewed to check for possible MS inclusions. Ten articles were found with a population consisting of patients with overactive bladder (OAB) symptoms, among which some were diagnosed with MS. [29][30][31][32][33][34][35][36][37][38] In 5 articles TTNS and in the other 5 PTNS were sued as the intervention. All of these publications, except for 1, supported the beneficial effects of TNS in enhancing different parameters regarding the OAB symptoms. However, none of these articles reported data exclusive for MS patients; therefore, they are taken into consideration in our study.
The results are presented in Supplementary Table 1.

Meta-analysis of Nocturia
The meta-analysis of 6 studies, presented in Figure 4, showed that nocturia episodes are decreased significantly following TNS (MD: -1.41, 95% CI: -2.22 to -0.60, and P < .001). Percutaneous tibial nerve stimulation and TTNS subgroups each also reduced these episodes;

Discussion
The aim of our systematic review was to analyze the scientific evidence on the treatment of MS-induced NLUTD through PTNS or TTNS  Multiple sclerosis is a unique neurological disease. It manifests with a broad spectrum of clinical presentations. These symptoms are related with time and disease course. Lower urinary tract symptoms (LUTSs), which are highly prevalent in MS patients (affecting over 80% of patients), are closely intertwined with the location of the plaque, that is either intracranial or spinal. Even, in some cases, LUTSs are the primary manifestation of MS (in 10% of patients), and also patients' disability status is usually related to the severity of their symptoms.
Overactive bladder symptoms are the most frequently reported complaints. Urinary urgency (38%-99% of patients), increased urinary frequency (26%-82% of patients) and urge incontinence (27%-66% of patients), stress urinary incontinence (with a prevalence of 56%), and mixed urinary incontinence are among the mostly reported symptoms of patients with MS, which cause a significant decrease of QoL. By contrast, symptoms of the voiding phase are less frequent (6%-49%). Symptoms of both the storage and voiding phases can coexist in 50% of patients. 10 Urinary tract is regulated by the medial prefrontal cortex, insula, and pons, and lesions in cortical regions lead to detrusor overactivity (DO). In addition, spinal cord, and particularly suprasacral lesions that are common in MS patients, may cause DO by impacting the descending inhibition of bladder contraction. Reticulospinal tract damage may lead to detru sor-s phinc ter-d yssyn ergia (DSD). Urinary retention may result from plaques that obstruct emptying in the efferent or afferent pathways. Only 5% of patients with sacral lesions have bladder areflexia, despite the fact that 63% of them exhibit detrusor hypocontractility. 39 Litwiller et al, in a meta-analysis, showed that 62% of MS patients had Neurogenic detrusor overactivity (NDO). The other signs were DSD (25%), and Detrusor underactivity (DU) (20%). In addition, 10% were normal on examination. Low bladder capacity, increased PVR volume, and increased DO amplitude are common in MS patients. As MS is a fluctuating disease, and often presents in recurring attacks, in which the symptoms become worse or new symptoms appear, and between attacks, Urodynamic studies (UDS) shows urinary tract function at particular time points despite the fact that the symptoms may get better or stay the same. 3 Different studies reported various prevalence of urinary symptoms in MS patients. A prevalence of 37%-99% for OAB, characterized by irritative bladder symptoms, 34%-79% for obstructive symptoms, and 25% for chronic urinary retention was reported. 6 Management of MS-induced NLUTD requires a multidisciplinary model. Some of the most common approaches are medical therapies, such as antimuscarinics, intermittent self-catheterization, the use of synthetic antidiuretic hormone desmopressin, cannabinoids, and intravesical treatments like Onabotulinum toxin A (BoNTA) injection. Other therapeutic approaches are neuromodulation, including TNS and sacral nerve stimulation (SNS), and surgical treatments such as cystoplasty and non-continent urinary diversion. 10 After behavioral therapies and medication management, nerve stimulation and neuromodulation is the third-line therapy used to treat these patients. 40 Although the exact mechanism of TNS or sacral nerve root S3 stimulation in managing OAB remains uncertain, its efficacy has been proved. However, it is thought to be a result of modulation of spinal pelvic reflexes through the activation of inhibitory interneurons. 41 The effects of TNS for NLUTD and OAB syndrome have also been the subject of multiple systematic reviews in the recent literature. [42][43][44][45] However, just 1 systematic review that examined the impact of PTNS on MS-induced NLUTD in patients with MS was published, and the findings were favorable. 46 The effects of TTNS on female MS patients with OAB syndrome have also been the subject of a protocol for a systematic review; however, its results have not yet been made public. 47 The unique aspect of our study is the combination of these 2 approaches, which closes this knowledge gap and tackles both PTNS and TTNS in MS patients, offering fresh perspectives on the overall impacts of cutting-edge neuromodulation techniques. 48

Limitations
Despite providing level 1 evidence, this study may be subject to bias, primarily due to the inclusion of nonrandomized and uncontrolled trials with limited populations. Second¸ none of the studies addressed the long-term efficacy of the TNS; therefore, it is yet unknown whether the improvement of NLUTD is lifelong, and generalizing the results to clinical settings is rather restricted.

Conclusion
The results of the current systematic review showed that stimulation of the tibial nerve shows a promising future in managing NLUTD in MS patients. However, due to the high heterogeneity among studies, these results must be interpreted with caution. The long-term effects of TNS therapy and its cost-effectiveness need to be addressed further by high-quality and controlled trials.